Histone acetyltransferases inhibitors

As say s for the identification and evaluation of histone acetyltransferase inhibitors. Methods (San Diego, Calif), 26, 245-253. 

Balasubramanyam, K., Altaf, M. and Varier, R.A. (2004) Polyisoprenylated benzophenone, garcinol, a natural histone acetyltransferase inhibitor, represses chromatin transcription and alters global gene expression. The Journal of Biological Chemistry, 279, 33716-33726. 

As an example of interest of these structures, the quinoline 57 (X=CH, Y = H) is known as histone acetyltransferase inhibitor and also a building block for tiie synthesis of lavendamycin analogue 58 (Figure 17). 

Despite the complexity of the experiments and the enormous data manipulation necessary, complex biological pathways, as well as new drug targets are being identified by this method. Examples include screens for compounds that arrest cells in mitosis, that block cell migration, and that block the secretory pathway [50], or assays with primary T cells from PLP TCR transgenic mice for their inhibitory activity on the proliferation and secretion of proinflammatory cytokines in PLP-reactive T cells [51], and identification of small-molecule inhibitors of histone acetyltransferase activity [52]. 

Several small molecule modulators (SMM) of p300 and PCAF have been developed (Varier et al, 2004). Recently, the first naturally occurring HAT inhibitor anacardic acid was isolated from cashew nut shell liquid, which inhibits the HAT activity of both p300 and PCAF very effectively (Balasubramanyam et al, 2003). By using anacardic acid as a synthon, an amide derivative of anacardic acid, CTPB, has been synthesized, which is the only known small molecule activator of any histone acetyltransferase, in this case, p300. However, cells are impermeable or... 

Balasubramanyam K, Swaminathan V, Ranganathan A, Kundu TK (2003) Small molecule modulators of histone acetyltransferase p300. J Biol Chem 278(21) 19134-19140 Barlow AL, van Drunen CM, Johnson CA, Tweedie S, Bird A, Turner BM (2001) dSIR2 and dHDAC6 two novel, inhibitor-resistant deacetylases in Drosophila melanogaster. Exp Cell Res 265(1) 90-103... 

Varier RA, Swaminathan V, Balasubramanyam K, Kundu TK (2004) Implications of small molecule activators and inhibitors of histone acetyltransferases in chromatin therapy. Biochem Pharmacol... 

Lachner M, O Carroll D, Rea S, Mechtler K Jenuwein T (2001) Methylation of histone H3 lysine 9 creates a binding site for HPl proteins. Nature 410 116-120 Lau OD, Kundu TK, Soccio RE, Ait-Si-Ali S, KhaUl EM, Vassilev A, Wolffe AP, Nakatani Y, Roeder RG, Cole PA (2000) HATs off selective synthetic inhibitors of the histone acetyltransferases p300 and PCAF. Mol Cell 5 589-595... 

Biel M, Kretsovali A, Karatzali E, Papamatheakis J, Giannis A (2004) Design, synthesis, and biological evaluation of a small-molecule inhibitor of the histone acetyltransferase Gcn5. Angew Chem Int Ed Engl 43(30) 3974-3976... 

Cole, P.A. and Marmorstein, R. (2002) Structure of the GCN5 histone acetyltransferase bound to a bisubstrate inhibitor. Proceedings of the National Academy of Sciences of the United States of America, 99 (22), 14065—14070. 

Turlais, F., Hardcastle, A., Rowlands, M., Newbatt, Y. Bannister. A., Kouzarides. T.. Workman, P. and Aherne, G.W. (2001) High-throughput screening for identification of small molecule inhibitors of histone acetyltransferases using scintillating microplates (FlashPlate). Aruilytical Biochemistry, 298, 62—68. 

Inhibitors of Histone Acetyltransferases Discovery and Biomedical Perspectives... 

Eliseeva, E.D., Valkov, V., Jung, M. and Jung, M.O. (2007) Characterization of novel inhibitors of histone acetyltransferases. Molecular Cancer Therapeutics, 6, 2391-2398. 

Stimson, L., Rowlands, M.G., Newbatt, Y.M., Smith, N.F., Raynaud, F.I., Rogers, P. et al. (2005) Isothiazolones as inhibitors of PCAF and p300 histone acetyltransferase activity. Molecular Cancer Therapeutics, 4, 1521—1532. 

Curcumin has also been found to interrupt the cell cycle, to have cytotoxic effects, and to have a role in antiproliferation and the induction of apoptosis in a hepatocarcinoma cell line. Curcumin is a potent inhibitor of phenol sulfotransferase (SULT1A1) in human liver and extrahepatic tissues [Vietri et al., 2003]. Curcumin inhibited the interleukin-6 (IL-6) production, histone acetyltransferase (HAT) activity, and API activation [Chen et al., 2003a] and prevented cell death and apoptotic biochemical changes, such as the... 

Balasubramanyam K, Varier RA, Altaf M, Swaminathan V, Siddappa NB, Ranga U, Kundu TK. 2004. Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription. J Biol Chem 279 51163-51171. 

AdoMet-Dependent Methyltransferases, Chemistry of DNA, Covalent Modifications of Histone Acetyltransferases, Selective Inhibitors of Post-Translational Modifications to Regulate Protein Eunction... 

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